# Genome Instability and Somatic Mutagenesis in Autoimmune Diseases

## TL;DR

This review explores how genome instability and somatic mutations in autoimmune diseases may contribute to cancer development and disease progression.

## Contribution

The paper highlights the link between inflammation, DNA damage, and somatic mutagenesis in autoimmune diseases, proposing a novel perspective on their role in carcinogenesis.

## Key findings

- Autoimmune diseases are associated with heightened inflammation and DNA damage, leading to genome instability.
- Somatic mutations in immune cells within autoimmune disorders may contribute to cancer development.
- The review provides examples of autoimmune diseases where mutagenesis has been studied in detail.

## Abstract

Autoimmune disorders (AID) are complex, multifactorial, and pervasive human health conditions that affect people globally. Nearly all AID are characterized by heightened inflammation and a breakdown of immune regulation, resulting in a loss of tissue homeostasis. Additionally, the hyper-inflammatory environment observed in AID is ideal for triggering neoplasia, resulting in various forms of cancer and further complicating disease treatment. Within the dysregulated immune microenvironment underlying AID, there is abundant DNA damage and genome instability. We posit that recurrent cycles of inflammation and DNA damage can result in stochastically elevated levels of somatic mutations in autoimmune disorders, and contribute to downstream malignancies. Understanding AID-associated DNA damage and mutagenicity would illuminate mechanisms that would subsequently inform disease prognosis, pathology, and progression. We explore this theme in our review by highlighting studies linking AID with genome instability and mutations, and carcinogenesis.

The adaptive immune system plays a vital role in protecting individuals against invading pathogens primarily through its ability to discern self- versus non-self-antigens. Conditions leading to the breakdown of such immune surveillance can have devastating consequences, one of them being erroneous recognition and immune response against self-antigens, resulting in autoimmunity. Autoimmune diseases (AID) are widespread and span multiple organ systems and cellular functions. Historically, the etiology of AID is multifarious and complex owing to a mix of genetic predisposition and environmental conditions. However, in recent years the study of somatic mutations has gained traction in understanding the basis of AID. Somatic mutations commonly result from elevated DNA damage and inefficient DNA repair and have been linked to cancer. Moreover, the hyper-inflammatory microenvironment is highly conducive to the accumulation of DNA damage in immune cells. Thus, understanding the mutational burden and landscape of somatic mutagenesis in the context of AID can illuminate the basis of disease development and progression. In this review, we summarize past and current research on genome instability in AID, focusing on the nexus between inflammation, immune response, DNA damage, and mutagenesis, and discuss the possible link between AID and cancer development. We provide examples of autoimmune disorders that have been studied from a mutational standpoint and outline results from key studies highlighting the extent of DNA damage and mutagenesis in cells from AID patients. Lastly, we provide our perspective on the key challenges and future directions to understand the role of somatic mutagenesis in autoimmunity and cancer.